Source Citation

Abstract

Question

In critically ill patients suspected of having ventilator-associated pneumonia (VAP),
does the diagnostic method used affect mortality and antibiotic use?

Methods

Design: Randomized controlled trial.

Allocation: Concealed.*

Blinding: Unblinded.*

Follow-up period: 28 days or to hospital discharge.

Setting: 28 intensive care units (ICUs) in Canada and the United States.

Patients: 740 critically ill patients ≥ 18 years of age (mean age 59 y, 69% men) who had
received mechanical ventilation in the ICU for ≥ 4 days and were suspected of
having VAP. Patients were excluded if they were immunocompromised, unsuitable for
bronchoscopy, or infected or colonized with Pseudomonas species or methicillin-resistant Staphylococcus aureus.

Intervention: Bronchoalveolar lavage (BAL) with quantitative culture of the bronchoalveolar-lavage
fluid (n = 365) or endotracheal aspiration (ETA) with nonquantitative culture of the
aspirate (n = 375). Empirical intravenous antibiotic therapy (meropenem, 1 g every 8 h,
with or without ciprofloxacin, 400 mg every 12 h, randomly assigned) was initiated
in all patients until culture results were available, at which time a protocol of
targeted therapy was to be used.

Outcomes: 28-day mortality, ICU and hospital mortality and length of stay, duration of mechanical
ventilation, and use of targeted therapy after culture results were known.

Patient follow-up: 99.9% (intention-to-treat analysis).

Main results

A positive culture was identified in 60% of patients in the BAL group and 52% in the
ETA group (P = 0.03). Groups did not differ for 28-day, ICU, or hospital mortality; use of
targeted therapy by day 6 (Table); or rates of clinical and microbial cure at 28 days.
The BAL and ETA groups had similar median durations (after randomization) of mechanical
ventilation (8.9 vs 8.8 d, P = 0.31), ICU stay (12 vs 12 d, P = 0.22), and hospital stay (40 vs 47 d, P = 0.13).

Conclusion

In critically ill patients suspected of having ventilator-associated pneumonia, a
diagnostic strategy using bronchoalveolar lavage with quantitative culture was associated
with mortality and overall antibiotic use similar to that of a strategy based on endotracheal
aspiration with nonquantitative culture.

Commentary

The study by the Canadian Critical Care Trials Group (CCCTG) is the largest to date
to compare “invasive” (i.e., bronchoscopic BAL and quantitative cultures) and “noninvasive”
(i.e., ETA and nonquantitative cultures) sampling techniques to diagnose VAP. The
study found no evidence of superiority of the invasive approach, contrary to the results
of the second largest study done in France (1).

The CCCTG trial used a factorial design to evaluate both the diagnostic approach and
antibiotic therapy (single vs combination), assuming that the 2 interventions would
not interact. However, using a fixed empirical regimen is problematic because acting
on early culture results is an integral part of the “invasive” strategy, which was
used in the French study. Indeed, the 2 studies differed in several important respects.
In the CCCTG trial, BAL fluid culture was considered positive if a potential pathogen
was isolated, regardless of the colony count, which probably explains both the unexpected
finding of a higher rate of positive BAL fluid cultures and the very high proportion
of patients (85%) classified as having pneumonia. Furthermore, Gram stains were used
in part to initiate therapy and early cultures were used to adapt therapy in both
groups of the French trial, whereas all patients in the CCCTG trial received broad-spectrum
therapy for a median of 3 days. Finally, the CCCTG trial excluded patients known to
be colonized with “high-risk” organisms; however, it is in this more difficult-to-treat
population that the invasive–quantitative techniques may be most useful.

While ample evidence exists that early appropriate treatment of patients with sepsis
is important, broad-spectrum antibiotic coverage for all patients clinically suspected
of pneumonia is questionable. As many as half such patients may not have overt sepsis
or even pneumonia. When all patients with suspected VAP receive broad-spectrum antibiotic
coverage for several days, the outcome is mainly driven by the adequacy of the empirical
regimen and is unlikely to be affected by culture results. Although the CCCTG study
adds to our knowledge, it does not provide a definitive answer to the respective value
of alternative strategies for diagnosing VAP.